Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are nuclear medicine techniques that enable the study of neurotransmitter receptors in living animals and humans, but the lack of suitable radiotracers for some neurotransmitter systems has limited the usefulness of these techniques. In the past year, a program to synthesize new radiotracers for nicotinic acetylcholine receptors (nAChRs) was implemented. Two epibatidine [(+/-)-exo-2-(2- chloro-5-pyridyl)-7-azabicyclo[2.2.1] heptane] derivatives, the 2-iodo and 2-[F-18]fluoro analogs, displayed high affinity for nAChRs. The synthesis of both radioiodinated [I-125]IPH and [I-123] yielded high specific activities. Autoradiographic and external probe studies demonstrated that [I-125]IPH was rapidly taken up by the brain, bound to nAChRs, had a slow clearance, but was not detectable after 24 h. A preliminary, primate SPECT study showed [I-123]IPH was localized in nAChR-rich areas of brain and was displaced by a nicotinic agonist. For these reasons, we believe that [I-125]IPH will be a very useful radioligand to study neuronal nAChRs in brain using SPECT. In addition to [F-18]FPH, we also synthesized the C-11 enantiomers of A-84543, a 3-pyridyl ether. All three radiotracers activate neuronal nAChRs. Their high specific activity (2000 mCl/umol) thus provides positron emitting radiotracers that are suitable for PET measurement of nAChRs. Another goal has been to improve our quantitative analysis of PET data for assaying receptor-ligand binding. Using modeling techniques, which involved analysis of both experimental [C-11]-raclopride PET data as well as computer-simulated data, we concluded that: (a) in vivo measurement of binding potential (BP) was adversely biased by the injection of too much mass of receptor ligand, (b) in practice, the mass doses commonly used are 'too much', (c) this effect of mass can be theoretically predicted, and (d) the unwanted correlation of BP estimates with mass can be eliminated by a simple correction technique requiring two PET scans.